Short, synthetic peptides that disrupt bacteria's response to antibiotics boost antibiotic activity against high-density skin infections in mice, according to new research presented by Daniel Pletzer and colleagues at the University of British Columbia in Vancouver, Canada.
Every year, bacterial infections of skin and soft tissue result in 3.2 million emergency department visits in the U.S. These high-density infections often involve bacteria that are resistant to multiple antibiotics, and can therefore be quite difficult to treat. While much research has addressed antibiotic resistance, few studies have focused on high-density infections of skin and soft tissues, which often form painful pockets of pus known as abscesses.
To address this issue, Pletzer and colleagues tested a strategy to enhance antibiotic activity against high-density infections in mice. They had previously shown that certain synthetic peptides -- short chains of amino acids (the building blocks of proteins) - could reduce the number of bacteria in mouse abscesses, as well as the size of the abscesses themselves.
In the new study, the researchers first infected mice with seven of the most difficult-to-treat bacteria found in human abscesses and confirmed that antibiotic treatment had poor efficacy against these infections. Then, they combined the antibiotics with the previously studied synthetic peptides and found that, compared to antibiotics given alone, the combination significantly reduced the number of infecting bacteria and the size of the abscesses. A peptide called DJK-5 was particularly effective.
Further research suggested that the peptides boosted antibiotic activity by increasing the permeability of the outer membrane of the bacterial cells, amplifying their uptake of the antibiotics. The peptides also appeared to disrupt the microbes' natural response to stressors like antibiotics, which controls their virulence and resistance to antibiotics.
These findings could help improve understanding of high-density infections in humans and inform development of better treatment strategies. Next steps for this field include testing other possible combinations of antibiotics and peptides to determine which are most effective, and further research into the molecular processes involved in the synergy between peptides and antibiotics.
"We have taken the most recalcitrant and resistant bacteria in our society in the most challenging of situations involving high density infections," the authors explain, "and shown that we can sensitize them to treatment with antibiotics using peptides that target stress responses in bacteria."
In your coverage please use this URL to provide access to the freely available article in PLOS Pathogens: http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1007084
Citation: Pletzer D, Mansour SC, Hancock REW (2018) Synergy between conventional antibiotics and anti-biofilm peptides in a murine, sub-cutaneous abscess model caused by recalcitrant ESKAPE pathogens. PLoS Pathog 14(6): e1007084. https://doi.org/10.1371/journal.ppat.1007084
Funding: Research reported in this publication was supported by a grant from the Canadian Institutes for Health Research FDN-154287, the National Institute of Allergy and Infectious Diseases (NIAID) of the U. S. National Institutes of Health under Award Number R33AI098701, and the Intramural Research Program of the NIAID. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. DP received a Feodor Lynen postdoctoral fellowship from the Alexander von Humboldt Foundation (Germany) as well as a Cystic Fibrosis Postdoctoral fellowship (Canada). SCM received the Centre for Blood Research (CBR) graduate student award as well as the Gerhard Henrik Armauer-Hansen Memorial Scholarship. REWH holds a Canada Research Chair in Health and Genomics and a UBC Killam Professorship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: The peptides described here have been filed for patent protection, assigned to REWH's employer the University of British Columbia, and licenced to ABT Innovations Inc. in which the University of British Columbia and REWH own shares.